Related Experiment Video

Updated: Jun 2, 2026

Through the Looking Glass: Time-lapse Microscopy and Longitudinal Tracking of Single Cells to Study Anti-cancer Therapeutics
06:00

Through the Looking Glass: Time-lapse Microscopy and Longitudinal Tracking of Single Cells to Study Anti-cancer Therapeutics

Published on: May 14, 2016

CYLD inhibits tumorigenesis and metastasis by blocking JNK/AP1 signaling at multiple levels

Paula Miliani de Marval1, Shazia Lutfeali, Jane Y Jin

  • 1Department of Dermatology, Duke University, Durham, North Carolina, USA.

Cancer Prevention Research (Philadelphia, Pa.)
|April 12, 2011
PubMed

Insights

A deficient CYLD mutant promotes skin cancer and metastasis by activating the JNK/AP1 pathway. Inhibiting JNK significantly reduces tumor development and metastasis in mice, revealing CYLD

Area of Science:

  • Molecular Biology
  • Oncology
  • Dermatology

Background:

  • CYLD is a known tumor suppressor linked to various cancers, including skin tumors.
  • The precise molecular mechanisms of CYLD's role in skin cancer suppression remain largely unknown.
  • Understanding CYLD's function is crucial for developing targeted skin cancer therapies.

Purpose of the Study:

  • To elucidate the molecular mechanisms by which CYLD regulates skin tumorigenesis.
  • To investigate the role of a catalytically deficient CYLD mutant (CYLD(m)) in skin cancer development.
  • To identify novel molecular targets and pathways regulated by CYLD in epidermal cancers.

Main Methods:

  • Generation of transgenic mice expressing a patient-relevant, catalytically deficient CYLD mutant (CYLD(m)) in the epidermis.
  • Chemical induction of skin tumors using 7,12-dimethylbenz[α]anthracene (DMBA) and 12-O-tetradecanoylphorbol-13-acetate (TPA).
  • Pharmacological inhibition of c-Jun-NH2-kinase (JNK) pathway in vivo.
  • Exogenous expression of CYLD(m) and wild-type CYLD in human squamous cell carcinoma (SCC) cell lines (A431).
  • Analysis of cell growth, migration, tumor growth, and molecular signaling pathways including JNK and AP1.

Main Results:

  • Epidermal expression of CYLD(m) sensitized mice to DMBA/TPA-induced skin tumors, which were prone to malignant progression and metastasis.
  • Tumors in CYLD(m) mice exhibited increased activation of JNK and downstream AP1 proteins (c-Jun, c-Fos).
  • Pharmacological JNK inhibition significantly reduced tumor development and abolished metastasis in CYLD(m) mice.
  • Exogenous CYLD(m) enhanced SCC cell growth, migration, and tumor growth, while wild-type CYLD inhibited these processes.
  • CYLD(m) upregulated K63 ubiquitination of c-Jun and c-Fos, leading to sustained AP1 activation, whereas wild-type CYLD inhibited AP1 function.

Conclusions:

  • CYLD suppresses epidermal tumorigenesis by inhibiting the JNK/AP1 signaling pathway.
  • CYLD(m) promotes skin cancer progression and metastasis through sustained JNK/AP1 activation.
  • c-Jun and c-Fos are novel targets of CYLD, with CYLD controlling their ubiquitination status and subsequent AP1 activity.

More Related Videos

Exploring the Pharmacological Action and Molecular Mechanism of Salidroside in Inhibiting MCF-7 Cell Proliferation and Migration11:13

Exploring the Pharmacological Action and Molecular Mechanism of Salidroside in Inhibiting MCF-7 Cell Proliferation and Migration

Published on: June 9, 2023

Related Concept Videos

Inhibition of Cdk Activity02:34

Inhibition of Cdk Activity

The orderly progression of the cell cycle depends on the activation of Cdk protein by binding to its cyclin partner. However, the cell cycle must be restricted when undergoing abnormal changes. Most cancers correlate to the deregulated cell cycle, and since Cdks are a central component of the cell cycle, Cdk inhibitors are extensively studied to develop anticancer agents. For instance, cyclin D associates with several Cdks, such as Cdk 4/6, to form an active complex. The cyclin D-Cdk4/6 complex...
Inhibition of CDK Activity02:34

Inhibition of CDK Activity

The orderly progression of the cell cycle depends on the activation of Cdk protein by binding to its cyclin partner. However, the cell cycle must be restricted when undergoing abnormal changes. Most cancers correlate to the deregulated cell cycle, and since Cdks are a central component of the cell cycle, Cdk inhibitors are extensively studied to develop anticancer agents. For instance, cyclin D associates with several Cdks, such as Cdk 4/6, to form an active complex. The cyclin D-Cdk4/6 complex...
MAPK Signaling Cascades01:07

MAPK Signaling Cascades

Mitogen-activated protein kinase, or MAPK pathway, activates three sequential kinases to regulate cellular responses such as proliferation, differentiation, survival, and apoptosis. The canonical MAPK pathway starts with a mitogen or growth factor binding to an RTK. The activated RTKs stimulate Ras, which recruits Raf or MAP3 Kinase (MAPKKK), the first kinase of the MAPK signaling cascade. Raf further phosphorylates and activates MEK or MAP2 Kinases (MAPKK), which in turn phosphorylates MAP...
Interactions Between Signaling Pathways01:19

Interactions Between Signaling Pathways

Signaling cascades usually lack linearity. Multiple pathways interact and regulate one another, allowing cells to integrate and respond to diverse environmental stimuli.
Convergence and divergence, and cross-talk between signaling pathways
Two distinct signaling pathways can converge on a single functional unit, which may either be a single protein or a complex of proteins. The response is either functionally distinct or synergistic between the two pathways but different from the response...
Anaphase Promoting Complex00:50

Anaphase Promoting Complex

The stepwise destruction of specific proteins is necessary for the progression and completion of the cell cycle. Such proteins are ubiquitinated by ubiquitin ligases and then subsequently destroyed by the proteasome. The SCF (Skp1/Cullin/F-box) and the anaphase-promoting complex (APC) are two important ubiquitin ligases involved in cell cycle progression. While SCF is active throughout the cell cycle, APC gets activated during metaphase to anaphase transition. Cdc20 or Cdh1 binds to APC and...
Mitogens and the Cell Cycle02:38

Mitogens and the Cell Cycle

Mitogens and their receptors play a crucial role in controlling the progression of the cell cycle. However, the loss of mitogenic control over cell division leads to tumor formation. Therefore, mitogens and mitogen receptors play an important role in cancer research. For instance, the epidermal growth factor (EGF) - a type of mitogen and its transmembrane receptor (EGFR), decides the fate of the cell's proliferation. When EGF binds to EGFR, a member of the ErbB family of tyrosine kinase...